Inhibition of fast axonal transport and microtubule polymerization in vitro by colchicine and colchiceine

Edström, Anders; Hanson, Mats; Wallin, Margareta; Cederholm, Bo

doi:10.1111/j.1748-1716.1979.tb06468.x

Cited by 10 publications

(4 citation statements)

References 30 publications

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“…In order to distinguish between simple diffusion of rAAV-5 vectors from the MFB to the SNc and retrograde axonal transport, colchicine was injected into the MFB prior to rAAV-5 vector delivery. Colchicine blocks fast axonal transport by interfering with microtubule organization (14), and it has been used to inhibit retrograde transport of rAV and rAAV from the sciatic nerve to the spinal cord in mice and rats (4). In agreement with previous observations (15), the dose of colchicine applied in this study did not change the morphology of TH-positive neurons in the SNc (Fig.…”

Section: Transduction Of the Nigrostriatal Pathway After Vector Delivsupporting

confidence: 81%

Transduction Profiles of Recombinant Adeno-Associated Virus Vectors Derived from Serotypes 2 and 5 in the Nigrostriatal System of Rats

Paterna

Feldon

2004

J Virol

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We compared the transduction efficiencies and tropisms of titer-matched recombinant adeno-associated viruses (rAAV) derived from serotypes 2 and 5 (rAAV-2 and rAAV-5, respectively) within the rat nigrostriatal system. The two serotypes (expressing enhanced green fluorescent protein [EGFP]) were delivered by stereotaxic surgery into the same animals but different hemispheres of the striatum (STR), the substantia nigra (SN), or the medial forebrain bundle (MFB). While both serotypes transduced neurons effectively within the STR, rAAV-5 resulted in a much larger EGFP-expressing area than did rAAV-2. However, neurons transduced with rAAV-2 vectors expressed higher levels of EGFP. Consistent with this result, EGFP-positive projections emanating from transduced striatal neurons covered a larger area of the SN pars reticulata (SNr) after striatal delivery of rAAV-5, but EGFP levels in fibers of the SNr were higher after striatal injection of rAAV-2. We also compared the potentials of the two vectors for retrograde transduction and found that striatal delivery of rAAV-5 resulted in significantly more transduced dopaminergic cell bodies within the SN pars compacta and ventral tegmental area. Similarly, EGFP-transduced striatal neurons were detected only after nigral delivery of rAAV-5. Furthermore, we demonstrate that after striatal AAV-5 vector delivery, the transduction profiles were stable for as long as 9 months. Finally, although we did not target the hippocampus directly, efficient and widespread transduction of hippocampal neurons was observed after delivery of rAAV-5, but not rAAV-2, into the MFB.With the exception of rare inherited mutations in specific genes that segregate with familial forms of Parkinson's disease (PD) (24,29,30,42), the molecular causes of PD remain unknown. Pathologically, PD is caused by the progressive degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNc), which is accompanied by a corresponding decline of the neurotransmitter dopamine in the striatum (STR). As a consequence, PD patients present with resting tremor, bradykinesia, rigidity, and postural instability. Dopamine replacement therapy using L-dopa is the most frequent treatment for PD, but its beneficial effects wear off over time and severe side effects often occur. Surgical treatments such as pallidotomy, thalamotomy, or deep brain stimulation as well as cell transplantation therapies ameliorate some of the symptoms but do not inhibit ongoing neurodegeneration. With increasing knowledge about molecular mechanisms of neuron death (19), gene therapy may offer the potential to interfere with the pathophysiological mechanisms causing cell death in PD. Previous gene therapy studies in rodent and nonhuman primate models of PD assessed the protective potential of neurotrophic, antiapoptotic, antioxidative, and dopamine-restorative genes delivered by recombinant adenovirus (rAV) (8), lentivirus (28), herpes simplex virus (13), adeno-associated virus (rAAV) (22), or hybrid viral (9) vectors. Besides the cho...

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Section: Transduction Of the Nigrostriatal Pathway After Vector Delivsupporting

confidence: 81%

Transduction Profiles of Recombinant Adeno-Associated Virus Vectors Derived from Serotypes 2 and 5 in the Nigrostriatal System of Rats

Paterna

Feldon

2004

J Virol

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“…58,59 Since it binds to the colchicine-tubulin complex, it is suggested that colchicine binds at a site different from the colchicine site on tubulin. 60 Precolchicine (a colchicine-like compound with rearranged bond system; Fig. 4i) is not active.…”

Section: B Role Of the C Ringmentioning

confidence: 98%

Anti‐mitotic activity of colchicine and the structural basis for its interaction with tubulin

Bhattacharyya

Panda

Gupta

et al. 2007

Medicinal Research Reviews

439

319

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In this review, an attempt has been made to throw light on the mechanism of action of colchicine and its different analogs as anti-cancer agents. Colchicine interacts with tubulin and perturbs the assembly dynamics of microtubules. Though its use has been limited because of its toxicity, colchicine can still be used as a lead compound for the generation of potent anti-cancer drugs. Colchicine binds to tubulin in a poorly reversible manner with high activation energy. The binding interaction is favored entropically. In contrast, binding of its simple analogs AC or DAAC is enthalpically favored and commences with comparatively low activation energy. Colchicine-tubulin interaction, which is normally pH dependent, has been found to be independent of pH in the presence of microtubule-associated proteins, salts or upon cleavage of carboxy termini of tubulin. Biphasic kinetics of colchicines-tubulin interaction has been explained in light of the variation in the residues around the drug-binding site on beta-tubulin. Using the crystal structure of the tubulin-DAMAcolchicine complex, a detailed discussion on the pharmacophore concept that explains the variation of affinity for different colchicine site inhibitors (CSI) has been discussed.

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“…On the other hand, EIN and COL differ only in substitution at the O-10 atom (-H for EIN vs.-CH 3 for COL; for structures see Figure 4). The ability of EIN to disrupt microtubules is an order of magnitude lower than that of COL (Edstrom et al, 1979;Staretz and Hastie, 1993). Therefore, the finding that EIN does not affect expression and transcriptional activities of PXR, CAR, and GR receptors favors the hypothesis of cytoskeleton-dependent GR-PXR/CAR-P450s signaling.…”

Section: Discussionmentioning

confidence: 71%

Expression and transcriptional activities of nuclear receptors involved in regulation of drug-metabolizing enzymes are not altered by colchicine: Focus on PXR, CAR, and GR in primary human hepatocytes

et al. 2006

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Recent findings show that colchicine (COL) in submicromolar concentrations downregulates the expression of major drug-metabolizing P450 enzymes in human hepatocytes. Concomitantly, the expression of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) was diminished by COL, whereas expression of glucocorticoid receptor (GR) remained unaltered. A tentative mechanism is perturbation of the GR-PXR/CAR-CYP2/3 signaling cascade, resulting in restricted transcriptional activity of GR receptor by colchicine. In this work we focused on 10-demethylcolchicine (colchiceine; EIN), a structural analogue and a putative metabolite of COL that lacks tubulin-binding activity. We investigated the effects of EIN on the expression of PXR, CAR, and GR receptors in primary cultures of human hepatocytes. In contrast with the effects of COL, EIN does not alter the expression of PXR, CAR, and/or GR receptors mRNAs. In addition, EIN had no effects on transcriptional activities of PXR, CAR, and GR receptors in reporter gene assays using transfected cell lines. Considering that COL and EIN are structurally very close and differ only in their tubulin-binding activity, the data presented imply that the deleterious effects of COL on the GR-PXR/CAR-CYP2/3 cascade are primarily due to perturbation of the microtubule network. Our data support the idea of replacing COL by EIN, which is less toxic and does not interact with xenoreceptors.

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Inhibition of fast axonal transport and microtubule polymerization in vitro by colchicine and colchiceine

Cited by 10 publications

References 30 publications

Transduction Profiles of Recombinant Adeno-Associated Virus Vectors Derived from Serotypes 2 and 5 in the Nigrostriatal System of Rats

Transduction Profiles of Recombinant Adeno-Associated Virus Vectors Derived from Serotypes 2 and 5 in the Nigrostriatal System of Rats

Anti‐mitotic activity of colchicine and the structural basis for its interaction with tubulin

Expression and transcriptional activities of nuclear receptors involved in regulation of drug-metabolizing enzymes are not altered by colchicine: Focus on PXR, CAR, and GR in primary human hepatocytes

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